Process for the preparation of 16-methylene compounds of the pregnane series



.i rnt nice Patented Dec. 11, 1962 3 968,226 PRfiCESd FUR THE PiREPARATION F Iii-METH- YLENE CGMPGUNDEE 0F HE PREGNANE SERIES David Tani), Metnchen, Norman L. Wendler, Summit, and Robert D. Hotisommer, in, Metuchen, Ni, assignors to Merck Sr (10., line, Railway, Psi-3., a corporation of New Jersey No Drawing. Filed Dee. 22, 1961, Ser. No. 161,396 16 Ciaims. (Ci. 26ti-239.55)

This invention relates to an improved process for the preparation of lo-alkylene steroids of the pregnane series as well as the l6-lower alkyl-16,17-oxido intermediates thereof. More particularly, this invention relates to a novel two-step process for the conversion of 16-lower alkyl-A -steroids of the pregnane series to the corresponding 16-alkylene compounds whereby both the l6-alkylene end product and l6-lower alkyl 16,17-oxido intermediate are formed in high yield.

This application is a continuation-in-part of copending applications Serial No. 801,429, filed March 24, 1959, and

peroxide or with an alkyl hydroperoxide in the presence of a strong base, as for example, hydrogen peroxide in the presence of sodium hydroxide, to obtain the corresponding 16-lower alkyl-16,l7-oxido compound, which, upon contact with a hydrohalic acid such as hydrochloric acid, results in the formation of the 16-alkylene steroid compound.

The primary disadvantages of having to use a strong base in the first step of this process are (1) the resulting alkaline hydrolysis of any 21-ester groups present as well as (2) the danger of cleavage of the whole l7-side chain with the resulting loss of yield. In the second step of this process, the use of hydrohalic acids is likewise undesirable because of the formation of many unwanted yet closelyrelated steroid by-products from which it is difiicult to separate the desired 16-alkylene product without using elaborate chromatographic procedures. Thus, for example, the reaction of 9a-fluoro-11B,21-dihydroxy-1GB-methyl-l6a,17a-oxido-l,4-pregnadiene-3,20-dione 21 acetate with hydrogen chloride results in the production of a mixture of 1) 9rx-fiuoro-115,17a,21-trihydroxy-lo-rnethylene- 1,4-pregnadiene-3,ZO-dione ZI-acetate, (2) 9a-fluoro-11B, 17c,2l-trihydroxy-16-methyl 1,4,15 pregnatriene-3,20'- dione ZI-acetate, (3) 9a-fluoro-l1/3,21-dihydroxy-l6-methly-1,4,l4,l6-pregnatetraene-3,ZO-dione 21-acetate, and (4) 9a fiuoro-lS-chloro 11/3,2l-dihydroxy l6 methyl-1,4, 16-pregnatriene-3,ZO-dione 21-acetate. In view of these ditficulties, it Was desirable to find a process which would minimize the formation of by-products and thus enhance the yield of the desired lo-alkylene steroid product.

It has now been found in accordance with the present invention that 16-lower alkyl-A -steroids of the pregnane series may be converted to the corresponding lo-alkylene steroid compounds by reacting the 16-lower alkyl-A steroid starting material with an organic peracid of a strong carboxylic acid in the presence of an alkalinebuffering agent, and contacting the resulting 16-methyl-l6,17- oxido compound with a strong carboxylic acid to obtain the 16-alkylene steroid in high yield.

As starting materials in the present process, there are employed 1,6-lower alkyl-A -steroids represented by the partial formula:

CH2 0B.

wherein R is lower alkyl and P represents an unsaturated pregnane ring nucleus having an oxygen substituent, such as keto or hydroxyl at 0-11, hydrogen or halogen at G9, a keto group at C3 and unsaturation in the A ring at C-4 or C-1 and C-4. The R group may be hydrogen but it is preferably an ester group derived from an organic carboxylic acid, especially such acids as formic, acetic, propionic, benzoic and the like. Typical examples of suitable 16-lower aIkyLA -steroid starting materials are:

In the first step of the present process, the ,16-lowcr alkyl-16,-l7-oxido compounds are prepared by reacting the l6-lower alkyl-A -starting material with an organic peracid of a strong carboxylic acid. Thus, peracids of formic acid, trichloroacetic acid, difluoroacetic acid and the like may satisfactorily be employed in this process, althrough peroxytrifluoroacetic acid has been found to be particularly effective in the conversion of the A -steroid to the corresponding l6oc,l7oc-0XidO compound. When peroxytrifiuoroacetic acid is employed, the reaction is conveniently carried out by dissolving the l6-1ower .a1kyl-A steroid in an inert organic solvent such as benzene, toluene suitable solvent such as acetone, ethyl acetate or acetoneether mixtures yields the 16-lower alkyl-16,17-oxido steroid.

in carrying out thisstep of the process, it has "been found desirable to employ about 1 mole of peracid for each mole of starting material in order to avoid reaction of the peroxytrifiuoroacetic acid with any other double bonds than the 16:17 double bond which may bepresent in the steroid nucleus.

The peroxytrifiuoroacetic acid reagent is conveniently prepared by adding trifiuoroacetic anhydride to a stirred solution of 90% hydrogen peroxide dissolved in methylene chloride. A fresh mixture of this reagent is then reacted with the steroid starting material.

In the second step of this process, the l6-lower alkyl- 16,17-oxido steroid is reacted with a strong carboxylic acid such as formic, chloroacetic, trichloroacetic, halogenated propionic acid, oxalic acid and the like to form the corresponding l6-methylene steroid. It has been found that trifluoroacetic acid is particularly effective in carrying out this reaction. Thus, the 16-lower alkyl- 16,17-oxido compound is conveniently reacted with trifiuoroacetic acid at room temperature for a period of about 1-3 hours. In general, while no additional solvent is necessary, it has been found that by carrying out this process in the presence of benzene, a purer product free of any l4,l6-diene by-product is obtained. The 16- alkylene-l7-hydroxy steroid product is conveniently recovered by chromatography over neutral alumina and Alternaelution with benzene-chloroform mixtures. tively, the reaction mixture may be extracted with methylene chloride, dried, and the residue crystallized from acetone, ether or acetone-ether mixtures.

In addition to the foregoing two-step process for the production of l6-alkylene steroids, this invention also contemplates the conversion of the 16-lower alkyl-A steroids to the corresponding 16-alkylene compound in a single step, thus eliminating the formation and isolation of the'intermediate 16,17-oxido compound. This is accomplished by reacting the 16-1ower alkyl-A -steroid dissolved in an inert organic solvent such as methylene chloride with a mixture of a percarboxylic acid and a carboxylic acid, as for example, a mixture of peroxytrifiuoroacetic acid and trifiuoroacetic acid, in the absence of any basic buffering agent. The reaction is conveniently carried out by stirring the reaction mixture at C. for about 10-30 minutes followed by further stirring at room temperature for 1-2 hours. After extracting the reaction mixture with methylene chloride and drying, the l6-alkylene-l7-hydroxy steroid is readily recovered by chromatography or crystallization.

The following examples illustrate methods of carrying 1 out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 To a stirred mixture of 2.00 g. of 16-methyl-21-hydroxy- 4,l6-pregnadiene-3,11,20-trione 2l-acetate and 30 g. of disodium hydrogen phosphate in 60 ml. of methylene chloride at 0 C. is added 10 ml. of 2.0 M peroxytrifiuoroacetic acid reagent (prepared by cautiously adding 5.1 ml. of trifluoroacetic anhydride to a stirred solution of 0.82 ml. 90% hydrogen peroxide in ml. of methylene chloride). After minutes at 0 C. and 1 hour at C., water is added and the mixture extracted with methylene chloride. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 16,8-methyl-16a,17aoxido-21-hydroxy-4-pregnene-3,11,20-trione 2 l-acetate.

In accordance with the foregoing procedure, but starting with l6-methyl-l1,8,2l-dihydroxy-4,l6-pregnadiene- 3,20-dione 2l-acetate there is obtained 16B-methyl- 1611,1701. oxido 113,2l-dihydroxy-4-pregnenc-3,20-dione ZI-acetate.

Example 2 To a stirred mixture of 2.00 g. of 906-flllOIO-16-l'll6ii1Yl- 21-hydroxy-4,16-pregnadiene-3,l1,20-trione 2l-acetate and g. of sodium bicarbonate in 60 ml. of methylene chloride at 0 C. is added 10 ml. of 2.0 M performic acid. After 10 minutes at 0 C. and 1 hour at 25 C., water is added and the mixture extracted with methylene chloride. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and 4 dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 9a-fiuoro-l6B-rnethyl- 16a,17aoxido-2l-hydroxy-4-pregnene-3,l1,20-trione 21- acetate.

In accordance with the foregoing procedure, but starting with 9st fluoro 16 methyl-1l/i,2l-dihydroxy-4,l6- pregnadiene-3,20-dione 2l-acetate there is obtained 9afluoro 16,6 methyl 16,l7a-oxido-11,3,21-dihydroxy-4- pregnene-3,20-dione 21-acetate.

Example 3 To a stirred mixture of 2.00 g. of l6-methyl-21-hydroxy-1,4,16-pregnatriene-3,l1,20-trione 2l-acetate and 30 g. of disodium hydrogen phosphate in 60 ml. of henzene at 0 C. is added 10 ml. of 2.0 M peroxytrifiuoroacetic acid reagent. After 10 minutes at 0 C. and 1 hour at 25 C., water is added and the mixture extracted with benzene. The organic extract is Washed with aqueous potassium bicarbonate, saturated sodium chloride and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 16,8-methyl-16a,l7aoxido-2l-hydroxy-1,4-pregnadiene-3,l1,20-trione 2l-acetate.

In accordance with the foregoing procedure, but startin g with 16-met'nyl-l1fi,21-dihydroxy-1,4,16-pregnatriene- 3,20-dione 21-acetate there is obtained 165-methyll6a,17 x oxido 115,21-dihydroxy-l,4-pregnadiene-3,20- dione 21-acetate.

Example 4 To a stirred mixture of 2.00 g. of 9ct-fluoro-16-methyl- 115,21-dihydroxy-L4,l6-pregnatriene-3,20-dione 2l-acetate and 15 g. of disodium hydrogen phosphate in 40 ml. of methylene chloride at 0 C. is added 5.0 ml. of 2.0 M peroxytrifiuoroacetic acid (prepared by adding 5.1 ml. of trifiuoroacetic anhydride to a stirred solution of 0.82 ml. hydrogen peroxide in 5 ml. of methylene chloride). After 1 hour at 0 C., water is added and the mixture extracted with methylene chloride. The organic extract is washed with water and saturated salt solution and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 9a-fluoro-16fi-methyl-l6a,17aoxido 115,21 dihydroxy-l,4-pregnadiene-3,20-dione 21- acetate.

In accordance with the foregoing procedure, but starting with 9oc-fluoro-l6-methyl-2l-hydroxy-1,4,16-pregnatriene-3,l1,20-trione 21-acetate there is obtained 9afluoro l6/3-methyl-16a,17u-oxido-2l-hydroxy-l,4-pregnadiene-3,11,20-trione 2l-acetate.

Example 5 To 240 mg. of 16fl-methyl-16a,l7rx-oxido-2l-hyroxy-4- pregnene-3,ll,20-trione Zl-acetate is added 3 ml. of trifluoroacetic acid mixed with 2 ml. of benzene. After 2 hours at 25 C., water is added and the mixture is extracted with methylene chloride. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 16 methylene 17a,2l-dihydroxy-4-pregnene-3,11,20-trione 2l-acetate.

In accordance with the foregoing procedure, but starting with 16B-methyl-l6oc,l7e-oxido-115,21-dihydroxy-4- pregnene-3,20-dione ZI-acetate there is obtained 16- methylene 11 8,170;,21-trihydroxy-4-pregnene-3,20-dione 21-acetate.

Example 6 To 240 mg. of 9e-fluoro-16,8-methyl-16a,17e-oxido-21- hydroxy-4-pregnene-3,l1,20-trione 2l-acetate is added 3 ml. of trichloroacctic acid. After 2 hours at 25 C., water is added and the mixture is extracted with methylene chloride. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 9a-fluoro-16-methylene-17a, 2l-dihydroxy-4-pregnene-3,11,20-trione 21-acetate.

In accordance with the foregoing procedure, but starting with 9a-fiuoro-l6B-methyl-16a,17o-oxido-l1fi,21-dihydroxy-4pregnene-3,ZO-dione ZI-acetate there is obtained 9a fluoro 16-methylene-1.15,17a,21-trihydroxy-4- pregnene-3,20-dione 21-acetate Example 7 To 240 mg. of 165-methyld6a,17a-oxido-21-hydroxy- 1,4pregnadiene-3,11,20-trione Ill-acetate is added 3 ml. of oxalic acid. After 2 hours at 25 C., water is added and the mixture is extracted with methylene chloride. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 16-methylene-17a,21-dihydroxy-l,4- pregnadiene-3,l1,20-trione 2l-acetate.

In accordance with the foregoing procedure, but starting with l6fi-methyl-16u,17o -oxido-1lB,21-dihydroxy-l,4- pregnadiene-3,20-dione 21-acetate there is obtained l6- methylene 11,3,170c,21 trihydroxy 1,4 pregnadiene- 3,20-dione 2l-acetate. i

Example 8 To a stirred solution of 1.00 g. of 9cc-fil10IO-16 3-II16111Y1- 16cc, l7u-oxido-l15,2l-dihydroxy-l,4-pregnadiene-3,20-dione 21-acetate in 20 ml. of benzene at C. is added a mixture of 4 ml. of trifluoroacetic acid and 10 ml. of benzene. After 18 hours at 2025 C. cold 5% sodium carbonate is added and the mixture extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. Crystallization of the solid residue from ethyl acetate gives 9a-fluoro-l6-methylene-l1 3, 17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione Zl-acetate.

Example 9 To a stirred mixture of 2.00 g. of 9a-fluoro-l6-rnethyl- 115,21 dihydroxy-4,16-pregnadiene-3,20-dione ZI-acetate in 60. ml. of methylene chloride at 0 C. is added 10 ml. of a mixture of peroxytrifluoroacetic acid reagent and trifiuoroacetic acid in a ratio of 1:1. After 10 minutes at 0 C. and 1 hour at 25 0, water is added and the mixture extracted with methylene chloride. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 90:- fluoro l6-methylene-1 1,8,17a,2l-trihydroxy-4,16-pregnadiene-3,20-dione 21-acetate.

In accordance with the foregoing procedure, but starting with 900 fluoro-16-methyl-11fi,21-dihydroxy-1,4,16- pregnatriene-lZO-dione ZI-acetate there is obtained 90:- fiuoro 16 methylene-11,8,17a,21-trihydroxy-1,4,16-pregnatriene-3,20 dione ZI-acetate.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. The process which comprises reacting a l6-lower alkyl-A -steroid of the pregnane series with a strong percarboxylic acid in the presence of an alkaline butfering agent, thereby forming the corresponding 16,8-lower alkyl-16oz,17a-0Xid0 steroid compound, and reacting this compound with a strong carboxylic acid to obtain the corresponding 16-lower alkylene-17-hydroxy steroid of the pregnane series.

2. The process which comprises reacting 16-methyl- 11B, 2 l -dihydroxy-4, l 6-pregnadiene-3,20-dione 21-acetate with peroxy trifluoroacetic acid in the presence of disodium hydrogen phosphate, thereby forming the corresponding 16fi-methyl-16a,l7a-oxido-steroid compound and reacting this compound with trifluoroacetic acid to obtain 16 methylene-1If ,17a,2l-trihydroxy-4-pregnene-3,20-dione 21-acetate 3. The process which comprises reacting 9a-fluoro-l6- methyl-1 1fl,21-dihydroxy-4,16-pregnadiene-3,20-dione 21- acetate with peroxytrifluoroacetic acid in the presence of disodium hydrogen phosphate, thereby forming the corresponding 16/3-methyl-16a,17a-oxido-steroid compound and reacting this compound with trifluoroacetic acid to obtain fluoro-16-methylene-l1,3,17a,21-trihydroxy-4- pregnene-3,20-dione 21-acetate.

'4. The process which comprises reacting 16-methyl- 1118,21 dihydroxy-1,4,l6-pregnatriene-3,ZO-dione 21-acetate with peroxytrifluoroacetic acid in the presence of disodium hydrogen phosphate, thereby forming the corresponding 16fi-methyl-16a,17a-oxido-steroid compound and reacting this compound with trifluoroacetic acid to obtain 16 methylene 11,8,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate.

5. The process which comprises reacting 9oc-fi11010-16- methyl 1 1,8,21-dihydroxy-1,4,16-pregnatriene-3,20-dione 21-acetate with peroxytrifluoroacetic acid in the presence of disodium hydrogen phosphate, thereby forming the corresponding 16,8 methyl :,170t-0Xid0-S16f0id compound and reacting this compound with trifluoroacetic acid to obtain 9a-fluoro-16-methylene-11B,17a,2 1-trihydroxy-l,4-pregnadiene-3,20-dione 21-acetate.

6. The process which comprises reacting a 16-lower alkyl-l1,21-bisoxygenated-A -steroid of the pregnane series with a strong percarboxylic acid in the presence of an alkaline buffering agent to form the corresponding 16,8-lower alkyl-l1,2l-bisoxygenated-l6u,17o-oxidosteroid compound.

7. The process according to claim 6, wherein the percarboxylic acid is peroxytrifluoroacetic acid and the buffering agent is disodium hydrogen phosphate.

8. The process according to claim 6 wherein the percarboxylic acid is performic acid and the buflfering agent is sodium carbonate.

9. The process according to claim 6 wherein the percarboxylic acid in peroxydifluoroacetic acid and the buifering agent is disodium hydrogen phosphate.

10. The process which comprises reacting a 16,8-lower alkyl-l1,21-bisoxygenated-16u,17o-oxido-steroid of the pregnane series with a strong carboxylic acid to obtain the corresponding 16'lower alkylene-17zx-hydroxy-steroid compound.

11. The process according to claim 10 wherein the reaction is carried out in the presence of the organic solvent benzene.

12. The process according to claim 10 wherein the carboxylic acid is trifluoroacetic acid.

13. The process according to claim 10 wherein the carboxylic acid is trichloroacetic acid.

No references cited. 

6. THE PROCESS WHICH COMPRISES REACTING A 16-LOWER ALKYL-11,21-BISOXYGENATED-$16-STEROID OF THE PREGNANE SERIES WITH A STRONG PERCARBOXYLIC ACID IN THE PRESENCE OF AN ALKALINE BUFFERING AGENT TO FORM THE CORRESPONDING 16B-LOWER ALKYL-11,21-BISOXYGENATED-16A,17A-OXIDOSTEROID COMPOUND. 